Lec5 Flashcards
Withdrawal Time
the period of time after drug administration during which the animal cannot be sent to market for slaughter as food and the eggs or milk must be discarded
Half Life
the time required for the amount of drug in the body to be reduced by 50% (usually expressed in hours and abbreviated T 1/2)
Steady State
the point at which drug accumulation and elimination are balanced
Pharmacokinetics
the study of the physiologic movement of drugs throughout the body; also includes the movement of substances across cell membranes.
The four steps in pharmacokinetics are:
Absorption
Distribution
Biotransformation
Excretion
Drug-blood/plasma levels are dependent upon
The rate at which the drug is absorbed into the blood stream.
The amount of drug that is absorbed into the blood stream.
The distribution of the drug throughout the body.
The biotransformation of the drug.
The rate and route of drug excretion.
Four basic mechanisms of drug movement across cell membranes include:
Passive Diffusion
Facilitated Diffusion
Active Transport
Pinocytosis/Phagocytosis
Passive Diffusion
movement of drug molecules from an area of high concentration to an area of low concentration
does not require or expend energy
drug molecules exchange at an even rate so there are equal numbers of molecules both inside and outside the cell
in theory, drug molecules move throughout the body until equilibrium is attained among all body compartments
requires the drug to dissolve in the cell membrane and pass through the cell membrane made primarily of phospholipid with small pores
Lipophilic (+some details of these drugs)
dissolves in fat or oil medium
Lipophilic drugs dissolve more readily into the phospholipid cell membranes such as the intestinal mucosa
Lipophilic drugs are well absorbed from the gut by passive diffusion
Hydrophilic (+some details of these drugs)
dissolves in water/aqueous medium
Do not pass through lipid rich membranes as easily
Are more readily absorbed in fluid surrounding cells and must diffuse through fluid to reach capillaries
Drugs given IM are ideally hydrophilic for better absorption
IM drugs may be formulated to be lipophilic in form for slower absorption
Ionization (how does this influence drugs/uptake)
also affects movement of drugs across cell membranes
Ionized drugs have either a positive or negative charge
Tend to be hydrophilic in form
Non-ionized drugs have no charge and are neutral
Tend to be lipophilic in form
What characteristics of water affinity and ionization lend to effective diffusion?
drug molecules that move most effectively across cell membranes are lipophilic/non-ionized
Facilitated Diffusion
like passive diffusion but utilizes a special carrier molecule
Carrier molecule helps drugs across the cell membrane
No energy is needed
Active Transport
specialized carrier molecules in cell membranes move the drug across the membrane
requires energy
can move against a concentration from areas of lower concentration to higher concentration
allows drugs to accumulate in high concentration within a cell or body compartment
Phagocytosis
cell eating that is helpful with large molecules such as proteins that cannot pass through intact membranes
Pinocytosis
cell drinking of liquid particles
Absorption
the passage of the drug from its site of administration into the bloodstream.
before drugs can reach the site of action, the membranes of the absorptive surfaces must be crossed
drugs that are directly administered into the blood supply do not have an absorptive phase because the drug is placed directly into the plasma compartment!
Bioavailability
the degree or percentage of a drug administered that actually enters the systemic circulation
reflects the route of administration and number of barriers the drug must cross and/or delays encountered in reaching therapeutic blood levels (IV>IM>SQ>PO)
drugs that have no barriers (would be considered 100% bioavailable (bioavailability number of 1)
drugs given IV or IA are 100% bioavailable
some drugs are designed to have poor or no bioavailability (topicals, local analgesics, oral dewormers)
the lower the bioavailability, the less drug in the circulation and tissues
factors that affects bioavailability include:
blood supply to the area
surface area of absorption
dosage form of the drug
mechanism of drug absorption
Drug factors that affect absorption are:
Drug Chemistry (lipophilic vs. hydrophilic)
Drug Size (smaller molecules pass easier)
Ionization of the drug (non-ionized pass phospholipid membranes, ionized diffuse through tissue fluid)
Acid-Base Characteristics (pH of the drug)
Ion Trapping
Drug Form
In an Acid Environment, an Acidic Drug is Predominately (ionization and water affinity)
Non-Ionized (Not Charged) and therefore Lipophilic
An Acid Drug in an Alkaline Environment is Predominately (ionization and water affinity)
Ionized and Hydrophilic
In an Alkaline environment, an Alkaline drug is (ionization and water affinity)
Non-ionized (Not Charged) and therefore Lipophilic
Alkaline Drugs in an Acid Environment are (ionization and water affinity)
Ionized (Charged) and therefore Hydrophilic
How does pH (drug/environment) affect ionization
The pH of a drug in the pH of an environment affects the ionization of that drug
Ion Trapping
drugs can pass from one compartment to another when the pH changes
When a drug changes compartments, it may become ionized and trapped in its new environment, so that it can be absorbed into the bloodstream
Ion trapping is especially important in drug excretion, since alterations in urine pH can allow drugs to be trapped in the urine and excreted
Drug Form
oral drugs must be lipophilic and small in size to penetrate the GI mucosa
Tablets must dissolve into smaller particles
Liquids do not have the dissolution step
Enteric coating alters dissolution and/or absorption
Decreased gastric motility lengthens absorption time
Increased gastric motility shortens absorption time (may pass into feces)
Presence of food may interfere with dissolution and absorption of certain drugs
May be detoxified by the liver due to the first pass effect
First Pass Effect
All blood that circulates to the small intestine must travel through the liver on its way to the systemic circulation via the hepatic portal system
This system allows the liver to remove potential toxins before they reach the general circulation
Some drugs are recognized as foreign substances and may be removed, thus preventing them from reaching the general circulation and tissues
Drugs that have an extensive first-pass effect are usually not recommended for PO use!
What water affinity must parenteral drugs be in?
hydrophilic form
Anything that interferes with drug diffusion from the administration site or alters blood flow to the injection site will delay absorption; what are they?
Limited blood flow at the injection site will slow absorption (fat vs. muscle)
Temperature will affect blood flow to the administration site (vasoconstriction vs. vasodilation)
Some drugs are formulated for delayed absorption (repository/depot injections)
Other drugs may affect blood flow and absorption
Patient factors that affect absorption are:
Age
Young animals may not have well developed GI tracts and less active enzyme systems
General health
Fever may increase movement of drug molecules
GI disease (vomiting/diarrhea) hinders absorption
Metabolic rate
Higher metabolic rates may cause more rapid drug metabolism and elimination
Genetic factors
Individual/species variation in response to drugs
Cats have a more rapid GI transit time
Sex
Males and females have different body fat compositions that may influence the absorption, and distribution of drugs
Distribution
the physiologic movement of drugs from the systemic circulation to the target tissues or site of action
Factors that affect distribution include
Membrane permeability and tissue perfusion
Protein Binding
Some drugs bind to proteins (albumin) in the blood and the large drug-protein complexes become trapped in the circulation
Animals with low protein levels will have less protein available for binding and more free drug available for the target tissues
Volume of Distribution
Drug concentration in the blood will lower if the drug has a large volume to distribute through
Diseases that produce extra body fluid (edema, ascites) will have less drug concentration in the blood and tissues due to a greater volume of distribution
Biotransformation or Metabolism
the chemical alteration of the drug molecules into metabolites by the body cells of the animal so that:
drugs are changed chemically into a “metabolite” form that can be active, inactive and/or toxic
metabolites are generally more ionized, hydrophilic and less chemically active so that they can be eliminated from the body
What is the primary organ of biotransformation; list the other places
The primary organ of biotransformation is the liver (cytochrome P450 of the hepatocytes)
Other locations include the lungs, skin, intestinal tract, kidney, nervous system
What are the four main pathways of biotransformation?
Oxidation, reduction, hydrolysis, conjugation
Factors affecting biotransformation include
Plasma protein binding
Less plasma protein binding allows excretion
Storage in tissue and fat
Liver disease
Less cytochrome P450
Species/Individual variation
Cats have decreased ability to form glucuronic acid
Route of administration
Some drugs cannot be given orally
Body temperature
Enzymes are temperature dependant
Age of patient
Very young or old due to liver status
Rumen pH changes with age
Nutritional status
Excretion or elimination
removal of drug from the body. Most drugs are excreted via the kidney into the urine.
Other routes of elimination include
the liver (first pass effect)
the lungs (anesthetic gases)
sweat/salivary glands (used in forensics)
milk (residue concerns for food safety)
intestinal tract (via bile and feces)
incorporation into hair, nails, hooves
Mechanisms of renal excretion include:
- Glomerular filtration (Non-selective,Highly dependant upon blood flow/pressure)
- Tubular secretion (Active transport across the convoluted tubule membrane, Moves molecules from blood into urine filtrate)
- Tubular reabsorption (Occurs in the loop of Henle, Drugs that are highly lipid soluble/non-ionized will have increased reabsorption)
Factors affecting excretion:
renal perfusion
clearance rate
half life
patient age
concurrent disease
percent of functioning nephrons
types of drugs/secondary drugs (concurrent diuretic use)
tubular reabsorption
Steady state
point at which drug accumulation and elimination are balanced
What ways can drugs interact with eachother
- Altered absorption (One drug affects another drug’s absorption) - Competition for plasma proteins (Two drugs may both bind to plasma, One displacing the other) - Altered excretion (drugs that act directly on the kidney may affect excretion) - Altered metabolism (drugs may need the same enzymes for biotransformation and decrease the rate of metabolism)
- Microsomal enzyme induction - some drugs cause liver enzymes to be more efficient (The drug’s rate of biotransformation is increased, Must monitor and increase dose periodically to maintain therapeutic blood levels)
- Tolerance – decreased response to a drug (
What are the two different types of tolerance?
Metabolic – drug metabolized quicker with chronic use
Cellular – “down regulation” or decreased cellular receptor response with repeated use
Where are the recepters drugs interact with located?
Receptors are three dimensional proteins or glycoproteins located located on:
Cell membrane surface
Cell cytoplasm
Within the nucleus
Tissue affinity and receptor sites
cell receptors bind to the drug molecules and then a response occurs through a structural-activity relationship between the drug and receptor
Affinity
the strength of binding between a drug and its receptor (measure of affinity is called the dissociation constant or KD)
Efficacy
the degree to which a drug has an exact fit to the receptor or produces the desired effect
Agonist
a drug that binds to a cell receptor and causes an action (has both affinity and efficacy)
Lock and Key comparison
similar to how drugs and receptors interact
Partial Agonist/Antagonist
A drug that binds to a cell receptor but has only partial effect (has affinity but only partial efficacy)
Antagonist
a drug that inhibits or blocks the response of the receptor site (has affinity but NO efficacy)
Competative Antagonist
competes for the same receptor
Non-competative Antagonist
binds to a different site than the agonist, but changes the shape of the agonist’s receptor, preventing the drug’s action
Non-Receptor Mediated Action
there are no cellular receptors with which the drug interacts(Osmotics and Chelators)
Osmotics
pull water from tissues and cells due to a molecular size or chemical effect that attracts water
Chelators
types of compounds used as drugs that physically combine with ions (e.g. Ca, Mg, Cl) or other specific compounds to produce their effects
Drug Interaction
an altered pharmacologic response to a drug that caused by the presence of a second (or more) drug
Adverse Drug Event
harm to a patient caused by drug administration for therapy or diagnosis
What are some causes of Adverse Drug Events?
- Due to medication errors such as wrong drug, wrong dose, wrong patient, etc.
- Due to an “adverse drug reaction” from the inherent properties of the drug itself such as poor drug quality or purity, reaction to the drug carrier, etc.
- Photosensitivity
- Other types of adverse drug reactions include vomiting, diarrhea, impaired hearing, organ damage (liver, kidney, heart), infertility/abortion, cancer, anaphylactic shock and death.
Photosensitivity Adverse Drug reaction
drugs that cause changes in the skin
Idiosyncratic Adverse Drug reaction
an unusual or unexpected reaction
Pharmaceutic Interaction
- physical or chemical reactions that occur as a result of mixing drugs in a syringe or container
- may precipitate or be altered when mixed and chemically inactivate the drug(s) or cause an adverse reaction
when should adverse drug reactions be reported
ALWAYS
All adverse drug reactions should be reported to the drug manufacturer or FDA.
the drug company is obligated to report the adverse reaction to the FDA
